Theranostics 2021; 11(2):941-957. doi:10.7150/thno.44948 This issue

Research Paper

Extra-domain B of fibronectin as an alternative target for drug delivery and a cancer diagnostic and prognostic biomarker for malignant glioma

Phei Er Saw1†, Xiaoding Xu1†, Bo Ram Kang3,4†, Jungsul Lee5, Yeo Song Lee3,4, Chungyeul Kim6, Hyungsin Kim7, Shin-Hyuk Kang7, Yoo Jin Na3,4, Hong Joo Moon4, Joo Han Kim4, Youn-Kwan Park4, Wonki Yoon4,8, Jong Hyun Kim4,8, Taek-Hyun Kwon4,8, Chulhee Choi5, Sangyong Jon2, Kyuha Chong3,4,8,9✉

1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
2. Department of Biological Sciences, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
3. Photo-Theranosis and Bioinformatics for Tumor Laboratory, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
4. Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
5. Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
6. Department of Pathology, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
7. Department of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Korea University College of Medicine, 73 Goryeodae-ro, Seoungbuk-gu, Seoul, 02841, Republic of Korea
8. Neurological Institute, Korea University Guro Hospital, Korea University Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
9. Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Saw PE, Xu X, Kang BR, Lee J, Lee YS, Kim C, Kim H, Kang SH, Na YJ, Moon HJ, Kim JH, Park YK, Yoon W, Kim JH, Kwon TH, Choi C, Jon S, Chong K. Extra-domain B of fibronectin as an alternative target for drug delivery and a cancer diagnostic and prognostic biomarker for malignant glioma. Theranostics 2021; 11(2):941-957. doi:10.7150/thno.44948. Available from https://www.thno.org/v11p0941.htm

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Abstract

Graphic abstract

Extra-domain B of fibronectin (EDB-FN) is an alternatively spliced form of fibronectin with high expression in the extracellular matrix of neovascularized tissues and malignant cancer cells. In this study, we evaluated the practicality of using EDB-FN as a biomarker and therapeutic target for malignant gliomas (MGs), representative intractable diseases involving brain tumors.

Methods: The microarray- and sequence-based patient transcriptomic database 'Oncopression' and tissue microarray of MG patient tissue samples were analyzed. EDB-FN data were extracted and evaluated from 23,344 patient samples of 17 types of cancer to assess its effectiveness and selectivity as a molecular target. To strengthen the results of the patient data analysis, the utility of EDB-FN as a molecular marker and target for MG was verified using active EDB-FN-targeting ultrasmall lipidic micellar nanoparticles (~12 nm), which had a high drug-loading capacity and were efficiently internalized by MG cells in vitro and in vivo.

Results: Brain tumors had a 1.42-fold cancer-to-normal ratio (p < 0.0001), the second highest among 17 cancers after head and neck cancer. Patient tissue microarray analysis showed that the EDB-FN high-expression group had a 5.5-fold higher risk of progression than the EDB-FN low-expression group (p < 0.03). By labeling docetaxel-containing ultrasmall micelles with a bipodal aptide targeting EDB-FN (termed APTEDB-DSPE-DTX), we generated micelles that could specifically bind to MG cells, leading to superior antitumor efficacy of EDB-FN-targeting nanoparticles compared to nontargeting controls.

Conclusions: Taken together, these results show that EDB-FN can be an effective drug delivery target and biomarker for MG.

Keywords: EDB-Fibronectin, Glioma, Big Data, Biomarkers, Micelles